Role of Fibroblast Growth Factor 23 in Patients with Chronic Kidney Disease
Fibroblast growth factor 23 (FGF23) is a critical hormone derived from osteocytes that plays a central role in regulating phosphorus and 1,25-dihydroxyvitamin D (1,25[OH]2D) metabolism. In patients with chronic kidney disease (CKD), FGF23 has emerged as a key biomarker and potential therapeutic target due to its involvement in mineral metabolism and its association with adverse clinical outcomes. This article provides a comprehensive overview of the role of FGF23 in CKD, including its physiological functions, regulatory mechanisms, clinical implications, and therapeutic potential.
Physiological Role of FGF23
FGF23 is a 251-amino acid protein secreted by osteocytes into the circulation after the cleavage of a 24-amino acid leader sequence. The intact form of FGF23 (iFGF23) can undergo further cleavage into two fragments: an N-terminal fragment and a C-terminal fragment (cFGF23). While iFGF23 is considered the biologically active form, cFGF23 is presumed to be inactive. FGF23 primarily regulates phosphate homeostasis by increasing renal phosphate excretion and suppressing the synthesis of 1,25(OH)2D. This creates a negative feedback loop, where elevated levels of 1,25(OH)2D and dietary phosphate upregulate FGF23 expression, which in turn reduces 1,25(OH)2D synthesis and phosphate absorption.
FGF23 in Chronic Kidney Disease
In patients with CKD, FGF23 is the earliest biochemical marker of disordered mineral metabolism, preceding increases in parathyroid hormone (PTH) and serum phosphate. As the estimated glomerular filtration rate (eGFR) declines, FGF23 levels rise, making it a valuable diagnostic marker for early CKD. Elevated FGF23 levels are strongly associated with poor clinical outcomes, including cardiovascular mortality and disease progression. A meta-analysis of 15 prospective cohort studies confirmed the positive correlation between FGF23 levels and cardiovascular mortality in CKD and dialysis patients, highlighting its potential as a prognostic biomarker.
FGF23 Fragments and Their Clinical Significance
The cleavage of FGF23 into its fragments has significant clinical implications. While iFGF23 is considered the bioactive form, cFGF23 has been shown to be a better predictor of disease progression in CKD. Studies have demonstrated that cFGF23 levels are higher in patients with lower eGFR and that elevated cFGF23 levels are associated with a more rapid decline in eGFR. However, conflicting evidence exists regarding the relationship between iFGF23 and cFGF23 during disease progression. Some studies suggest that iFGF23 levels increase as cFGF23 levels decrease, indicating reduced cleavage of the intact form. This highlights the need for further research to determine the specific roles of these fragments in CKD progression.
Mechanisms Regulating FGF23 Cleavage
The cleavage of FGF23 is influenced by several factors, including phosphate retention, iron deficiency, and erythropoietin (EPO) levels. Phosphate retention enhances the expression of GalNAc-transferase 3 (GALNT3), leading to O-glycosylation of iFGF23 and reducing its susceptibility to proteolysis by furin. Conversely, iron deficiency and EPO promote the cleavage of FGF23, resulting in elevated cFGF23 levels. Recent studies have also shown that hypoxia-inducible factor-proline hydroxylase inhibitors (HIF-PHIs) increase FGF23 levels, further complicating the regulatory mechanisms. Iron deficiency, mediated by HIF1α and EPO, independently increases FGF23 levels and promotes its cleavage, with these effects being dependent on renal function.
Therapeutic Implications of FGF23
Given its association with adverse outcomes, FGF23 has emerged as a potential therapeutic target in CKD. Correcting iron deficiency, a major determinant of elevated FGF23 levels, has been shown to reduce FGF23 levels. Oral iron supplementation has been found to be superior to intravenous iron in this regard, and iron-based phosphate binders have been particularly effective. These binders not only reduce serum phosphorus levels but also correct iron deficiency, thereby lowering FGF23 levels and potentially improving long-term outcomes. Additionally, recent studies suggest that blocking FGF23 signaling could prevent renal anemia in CKD, opening new avenues for therapeutic intervention.
Conflicting Evidence and Future Directions
Despite the growing body of evidence supporting the role of FGF23 in CKD, some conflicting findings highlight the need for further research. For instance, the biological activity of cFGF23 remains poorly understood, and its role in CKD progression is not fully elucidated. Future studies should focus on clarifying the mechanisms by which FGF23 promotes kidney dysfunction and identifying the most suitable FGF23 fragment for prognostic purposes. Additionally, the effects of therapeutic strategies aimed at controlling FGF23 levels, such as iron supplementation and phosphate binders, should be further investigated to determine their impact on clinical outcomes.
Conclusion
FGF23 plays a pivotal role in the pathophysiology of CKD, serving as an early biomarker of disordered mineral metabolism and a predictor of adverse outcomes. Its regulation by factors such as phosphate retention, iron deficiency, and EPO underscores the complexity of its role in CKD. While FGF23 holds promise as a therapeutic target, further research is needed to fully understand its mechanisms of action and to develop effective strategies for managing CKD. By addressing these gaps in knowledge, clinicians can better utilize FGF23 as a diagnostic and prognostic tool, ultimately improving patient outcomes in CKD.
doi.org/10.1097/CM9.0000000000001148
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